The projects aim is to study the biological role of the endothelin (Et) system which includes the Et peptide and its receptors. Specifically, the project will examine the hypothesis that each of the Et receptor subtypes, EtA and EtB, is uniquely modulated by the Et ligand and this modulation is distinct from the usual ligand-receptor interactions. Thus, Et has little effect on the EtA subtype. By contrast, Et upregulates the EtB subtype. Each receptor subtype, in turn, modulates production of the Et peptide itself, such that EtA exerts a negative feedback to decrease Et production while a positive feedback to increase Et production occurs through the EtB receptor subtype. The EtB receptor subtype may also suppress Et production through nitric oxide (NO) and prostacyclin (PGI2). The functional consequence of Et activation will then be determined by the contribution of the distinct function of each receptor system whereby EtA mediates vasoconstriction and EtB mediates vasoconstriction or vasodilation. The projects will also examine a physiologic modulator of this system, the adrenergic nervous system, as well as a pathophysiologic modulator, cyclosporine.